03-4969-r6 (8.5x11)/21/pdf

This information is intended for U.S. residents only.
DEPAKOTE® Tablets
DIVALPROEX SODIUM
DELAYED-RELEASE TABLETS
BOX WARNING:
HEPATIC FAILURE RESULTING IN FATALITIES HAS OCCURRED IN PATIENTS RECEIVING VALPROIC ACIDAND ITS DERIVATIVES. EXPERIENCE HAS INDICATED THAT CHILDREN UNDER THE AGE OF TWO YEARSARE AT A CONSIDERABLY INCREASED RISK OF DEVELOPING FATAL HEPATOTOXICITY, ESPECIALLYTHOSE ON MULTIPLE ANTICONVULSANTS, THOSE WITH CONGENITAL METABOLIC DISORDERS, THOSEWITH SEVERE SEIZURE DISORDERS ACCOMPANIED BY MENTAL RETARDATION, AND THOSE WITHORGANIC BRAIN DISEASE. WHEN DEPAKOTE IS USED IN THIS PATIENT GROUP, IT SHOULD BE USED WITHEXTREME CAUTION AND AS A SOLE AGENT. THE BENEFITS OF THERAPY SHOULD BE WEIGHED AGAINSTTHE RISKS. ABOVE THIS AGE GROUP, EXPERIENCE IN EPILEPSY HAS INDICATED THAT THE INCIDENCE OFFATAL HEPATOTOXICITY DECREASES CONSIDERABLY IN PROGRESSIVELY OLDER PATIENT GROUPS.
THESE INCIDENTS USUALLY HAVE OCCURRED DURING THE FIRST SIX MONTHS OF TREATMENT. SERI- OUS OR FATAL HEPATOTOXICITY MAY BE PRECEDED BY NON-SPECIFIC SYMPTOMS SUCH AS MALAISE,WEAKNESS, LETHARGY, FACIAL EDEMA, ANOREXIA, AND VOMITING. IN PATIENTS WITH EPILEPSY, ALOSS OF SEIZURE CONTROL MAY ALSO OCCUR. PATIENTS SHOULD BE MONITORED CLOSELY FORAPPEARANCE OF THESE SYMPTOMS. LIVER FUNCTION TESTS SHOULD BE PERFORMED PRIOR TO THER-APY AND AT FREQUENT INTERVALS THEREAFTER, ESPECIALLY DURING THE FIRST SIX MONTHS.
TERATOGENICITY:
VALPROATE CAN PRODUCE TERATOGENIC EFFECTS SUCH AS NEURAL TUBE DEFECTS (E.G., SPINABIFIDA), ACCORDINGLY, THE USE OF DEPAKOTE TABLETS IN WOMEN OF CHILDBEARING POTENTIALREQUIRES THAT THE BENEFITS OF ITS USE BE WEIGHED AGAINST THE RISK OF INJURY TO THE FETUS.
THIS IS ESPECIALLY IMPORTANT WHEN THE TREATMENT OF A SPONTANEOUSLY REVERSIBLE CONDI-TION NOT ORDINARILY ASSOCIATED WITH PERMANENT INJURY OR RISK OF DEATH (E.G., MIGRAINE) ISCONTEMPLATED. SEE WARNINGS, INFORMATION FOR PATIENTS.
AN INFORMATION SHEET DESCRIBING THE TERATOGENIC POTENTIAL OF VALPROATE IS AVAILABLE FORPATIENTS.
DESCRIPTION
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar rela-tionship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically itis designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Divalproex sodium occurs as a white powder with a characteristic odor.
DEPAKOTE tablets are for oral administration. DEPAKOTE tablets are supplied in three dosage strengths containing dival- proex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid.
Inactive Ingredients
DEPAKOTE tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch),
silica gel, talc, titanium dioxide, and vanillin.
In addition, individual tablets contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40.
250 mg tablets: FD&C Yellow No. 6 and iron oxide.
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its
therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain con-
centrations of gamma-aminobutyric acid (GABA).
Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of DEPAKOTE (divalproex sodium) products and DEPAKENE (valproic acid) capsules deliver equiva-
lent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation
administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g.,
whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor
clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon ini- tiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorptionof the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employingdosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rateinfusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure controland that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequentialfrom a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic orantimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various DEPAKOTE and DEPAKENE formulations should cause no clinical problems in the management of patients with epilepsy (see DOSAGE AND ADMIN-
ISTRATION). Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs
should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding:
The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately
10% at 40 µg/mL to 18.5% at 130 µg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic
diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may dis-
place certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide). (See PRECAUTIONS, Drug
Interactions for more detailed information on the pharmacokinetic interactions of valproate with other drugs.)
CNS Distribution:
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total con-
centration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose
appears in urine as a glucuronide conjugate. Mitochondrial ß-oxidation is the other major metabolic pathway, typically
accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less
than 3% of an administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportion- ally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drugare linear. EliminationMean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively.
Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminalhalf-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems.
For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clearvalproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should beintensified whenever concomitant antiepileptics are introduced or withdrawn.
Special PopulationsEffect of Age:Neonates - Children within the first two months of life have a markedly decreased ability to eliminate valproate compared toolder children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferaseand other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due todecreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months.
Children - Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e.,mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those ofadults.
Elderly - The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced com-
pared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%.
Accordingly, the initial dosage should be reduced in the elderly. (See DOSAGE AND ADMINISTRATION).
Effect of Gender:There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and4.7±0.07 L/hr per 1.73 m2, respectively).
Effect of Race:The effects of race on the kinetics of valproate have not been studied.
Effect of Disease:
Liver Disease - (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS). Liver disease impairs the capac-
ity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and
by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was
increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound frac-
tions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free con-
centrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be
normal.
Renal Disease - A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal fail-
ure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%.
Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is sub-
stantially reduced; thus, monitoring total concentrations may be misleading.
Plasma Levels and Clinical Effect
The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the
nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring oftotal serum valproate cannot provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 µg/mL to 18.5% at 130 µg/mL. Higher than expected free fractions occur in the elderly, in hyper-lipidemic patients, and in patients with hepatic and renal diseases. Epilepsy:The therapeutic range in epilepsy is commonly considered to be 50 to 100 µg/mL of total valproate, although some patientsmay be controlled with lower or higher plasma concentrations.
Mania:
In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations
between 50 and 125 µg/mL (See DOSAGE AND ADMINISTRATION).
Clinical Trials
Mania
The effectiveness of DEPAKOTE for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, par-
allel group studies.
(1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for Bipolar Disorder and who were hospital-
ized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treat-
ment. DEPAKOTE was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of
50-100 µg/mL by day 7. Mean DEPAKOTE doses for completers in this study were 1118, 1525, and 2402 mg/day at days
7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an aug-
mented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from
baseline in the week 3 endpoint (last-observation-carry-forward) analysis were as follows:
YMRS Total Score
Baseline1
BL to Wk 32
Difference3
BPRS-A Total Score
Baseline1
BL to Wk 32
Difference3
GAS Score
Baseline1
BL to Wk 32
Difference3
3 Difference in change from baseline to week 3 endpoint (LOCF) between DEPAKOTE and placebo DEPAKOTE was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who werehospitalized for acute mania. DEPAKOTE was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2500 mg/day to achieve serum valproate concentrations in a range of 40-150 µg/mL. Mean DEPAKOTE doses for com-pleters in this study were 1116, 1683, and 2006 mg/day at days 7, 14, and 21, respectively. Study 2 also included a lithiumgroup for which lithium doses for completers were 1312, 1869, and 1984 mg/day at days 7, 14, and 21, respectively. Patientswere assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the totalMRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and IdeationScale (BIS). Baseline scores and change from baseline in the week 3 endpoint (last-observation-carry-forward) analysis wereas follows: MRS Total Score
Baseline1
BL to Day 212
Difference3
MSS Total Score
Baseline1
BL to Day 212
Difference3
BIS Total Score
Baseline1
BL to Day 212
Difference3
3 Difference in change from baseline to day 21 endpoint (LOCF) between DEPAKOTE and placebo and lithium and placebo DEPAKOTE was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis forage and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1.
Percentage of Patients Achieving ≥ 30% Reduction in
Symptom Score From Baseline
* p < 0.05PBO = placebo, DVPX = DEPAKOTE Migraine
The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of
DEPAKOTE in the prophylactic treatment of migraine headache.
Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior toenrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from onestudy, but were permitted in the other if they were deemed to be practicing an effective method of contraception.
In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind con- ditions, to DEPAKOTE or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treat-ment phase.
In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, DEPAKOTE to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individu-alized at the investigator’s discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order tomaintain the study blind. In patients on DEPAKOTE doses ranged from 500 to 2500 mg a day. Doses over 500 mg were givenin three divided doses (TID). The mean dose during the treatment phase was 1087 mg/day resulting in a mean trough total val-proate level of 72.5 µg/mL, with a range of 31 to 133 µg/mL.
The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the DEPAKOTE group (see Figure 2). These rates were significantly different.
In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were random- ized equally to one of three DEPAKOTE dose groups (500, 1000, or 1500 mg/day) or placebo. The treatments were given intwo divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to bedetermined by a comparison of the 4-week migraine headache rate in the combined 1000/1500 mg/day group and placebogroup.
The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 µg/mL in the DEPAKOTE 500, 1000, and 1500 mg/day groups, respectively.
The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the DEPAKOTE 500, 1000, and 1500 mg/day groups, respectively,based on intent-to-treat results (see Figure 2). Migraine headache rates in the combined DEPAKOTE 1000/1500 mg groupwere significantly lower than in the placebo group.
Mean 4-week Migraine Rates
DEPAKOTE 1
DEPAKOTE 2
1 Mean dose of DEPAKOTE was 1087 mg/day.
2 Dose of DEPAKOTE was 500 or 1000 mg/day.
Epilepsy
The efficacy of DEPAKOTE in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in associa-
tion with other seizure types was established in two controlled trials.
In one, a multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who contin- ued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine orphenytoin sufficient to assure plasma concentrations within the “therapeutic range” were randomized to receive, in addition totheir original antiepilepsy drug (AED), either DEPAKOTE or placebo. Randomized patients were to be followed for a total of16 weeks. The following table presents the findings.
Adjunctive Therapy Study
Median Incidence of CPS per 8 Weeks
Baseline
Experimental
Treatment
of Patients
Incidence
Incidence
*Reduction from baseline statistically significantly greater for DEPAKOTE than placebo at p ≤ 0.05 level.
Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rateswas at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates animprovement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a displayof this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the pro-portion of patients achieving any particular level of improvement was consistently higher for DEPAKOTE than for placebo.
For example, 45% of patients treated with DEPAKOTE had a ≥ 50% reduction in complex partial seizure rate compared to23% of patients treated with placebo.
Improvement
No Change
% Reduction In CPS Rate
DEPAKOTE
Placebo
Worsening
% of Patients
The second study assessed the capacity of DEPAKOTE to reduce the incidence of CPS when administered as the sole AED.
The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qual-ified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine,phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to DEPAKOTE. Patients enter-ing the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED andfollowed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. Inpatients converted to DEPAKOTE monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 µg/mL in the low dose and high dose groups, respectively.
The following table presents the findings for all patients randomized who had at least one post-randomization assessment.
Monotherapy Study
Median Incidence of CPS per 8 Weeks
Baseline
Randomized Phase
Treatment
of Patients
Incidence
Incidence
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.
Figure 4 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rateswas at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improve-ment (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of thistype, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This figure showsthat the proportion of patients achieving any particular level of reduction was consistently higher for high dose DEPAKOTEthan for low dose DEPAKOTE. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidonemonotherapy to high dose DEPAKOTE monotherapy, 63% of patients experienced no change or a reduction in complex par-tial seizure rates compared to 54% of patients receiving low dose DEPAKOTE.
Improvement
No Change
% Reduction In CPS Rate
High Dose
Low Dose
Worsening
% of Patients
INDICATIONS AND USAGE
Mania
DEPAKOTE (divalproex sodium) is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic
episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania
include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgement, aggres-
siveness, and possible hostility.
The efficacy of DEPAKOTE was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania (See Clinical Trials under CLINICAL PHARMACOLOGY).
The safety and effectiveness of DEPAKOTE for long-term use in mania, i.e., more than 3 weeks, has not been systemati- cally evaluated in controlled clinical trials. Therefore, physicians who elect to use DEPAKOTE for extended periods shouldcontinually reevaluate the long-term usefulness of the drug for the individual patient.
Epilepsy
DEPAKOTE (divalproex sodium) is indicated as monotherapy and adjunctive therapy in the treatment of patients with com-
plex partial seizures that occur either in isolation or in association with other types of seizures. DEPAKOTE (divalproex
sodium) is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and
adjunctively in patients with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain gener- alized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are alsopresent.
Migraine
DEPAKOTE is indicated for prophylaxis of migraine headaches. There is no evidence that DEPAKOTE is useful in the acute
treatment of migraine headaches. Because valproic acid may be a hazard to the fetus, DEPAKOTE should be considered for
women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the
potential benefits of treatment (see WARNINGS - Usage In Pregnancy, PRECAUTIONS - Information for Patients).
SEE WARNINGS FOR STATEMENT REGARDING FATAL HEPATIC DYSFUNCTION.
CONTRAINDICATIONS
DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFI-CANT HEPATIC DYSFUNCTION.
Divalproex sodium is contraindicated in patients with known hypersensitivity to the drug.
WARNINGS
Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. These incidents usually have
occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific
symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver func-
tion tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all
instances, but should also consider the results of careful interim medical history and physical examination.
Caution should be observed when administering DEPAKOTE products to patients with a prior history of hepatic
disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe
seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk.
Experience has indicated that children under the age of two years are at a considerably increased risk of developing
fatal hepatotoxicity, especially those with the aforementioned conditions. When DEPAKOTE is used in this patient
group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against
the risks. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases
considerably in progressively older patient groups.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or appar-
ent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug.
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia [see PRECAUTIONS]) may
be dose-related. In a clinical trial of DEPAKOTE as monotherapy in patients with epilepsy, 34/126 patients (27%) receivingapproximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patientshad treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized withcontinued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate con-centrations of ≥ 110 µg/mL (females) or ≥ 135 µg/mL (males). The therapeutic benefit which may accompany the higher dosesshould therefore be weighed against the possibility of a greater incidence of adverse effects.
Usage In Pregnancy
ACCORDING TO PUBLISHED AND UNPUBLISHED REPORTS, VALPROIC ACID MAY PRODUCE TERATOGENIC
EFFECTS IN THE OFFSPRING OF HUMAN FEMALES RECEIVING THE DRUG DURING PREGNANCY.
THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE WHICH INDICATE THAT THE USE OF ANTIEPILEPTIC DRUGS DURING PREGNANCY RESULTS IN AN INCREASED INCIDENCE OF BIRTH DEFECTSIN THE OFFSPRING. ALTHOUGH DATA ARE MORE EXTENSIVE WITH RESPECT TO TRIMETHADIONE, PARA-METHADIONE, PHENYTOIN, AND PHENOBARBITAL, REPORTS INDICATE A POSSIBLE SIMILAR ASSOCIATIONWITH THE USE OF OTHER ANTIEPILEPTIC DRUGS. THE INCIDENCE OF NEURAL TUBE DEFECTS IN THE FETUS MAY BE INCREASED IN MOTHERS RECEIVING VALPROATE DURING THE FIRST TRIMESTER OF PREGNANCY. THE CENTERS FOR DISEASE CONTROL (CDC)HAS ESTIMATED THE RISK OF VALPROIC ACID EXPOSED WOMEN HAVING CHILDREN WITH SPINA BIFIDATO BE APPROXIMATELY 1 TO 2%.
OTHER CONGENITAL ANOMALIES (EG, CRANIOFACIAL DEFECTS, CARDIOVASCULAR MALFORMATIONS AND ANOMALIES INVOLVING VARIOUS BODY SYSTEMS), COMPATIBLE AND INCOMPATIBLE WITH LIFE,HAVE BEEN REPORTED. SUFFICIENT DATA TO DETERMINE THE INCIDENCE OF THESE CONGENITAL ANOM-ALIES IS NOT AVAILABLE.
THE HIGHER INCIDENCE OF CONGENITAL ANOMALIES IN ANTIEPILEPTIC DRUG-TREATED WOMEN WITH SEIZURE DISORDERS CANNOT BE REGARDED AS A CAUSE AND EFFECT RELATIONSHIP. THERE ARE INTRIN-SIC METHODOLOGIC PROBLEMS IN OBTAINING ADEQUATE DATA ON DRUG TERATOGENICITY IN HUMANS;GENETIC FACTORS OR THE EPILEPTIC CONDITION ITSELF, MAY BE MORE IMPORTANT THAN DRUG THER-APY IN CONTRIBUTING TO CONGENITAL ANOMALIES.
PATIENTS TAKING VALPROATE MAY DEVELOP CLOTTING ABNORMALITIES. A PATIENT WHO HAD LOW FIBRINOGEN WHEN TAKING MULTIPLE ANTICONVULSANTS INCLUDING VALPROATE GAVE BIRTH TO ANINFANT WITH AFIBRINOGENEMIA WHO SUBSEQUENTLY DIED OF HEMORRHAGE. IF VALPROATE IS USED INPREGNANCY, THE CLOTTING PARAMETERS SHOULD BE MONITORED CAREFULLY.
HEPATIC FAILURE, RESULTING IN THE DEATH OF A NEWBORN AND OF AN INFANT, HAVE BEEN REPORTED FOLLOWING THE USE OF VALPROATE DURING PREGNANCY.
Animal studies have demonstrated valproate-induced teratogenicity. Increased frequencies of malformations, as well as intrauterine growth retardation and death, have been observed in mice, rats, rabbits, and monkeys following prenatal exposureto valproate. Malformations of the skeletal system are the most common structural abnormalities produced in experimental ani-mals, but neural tube closure defects have been seen in mice exposed to maternal plasma valproate concentrations exceeding 230 µg/mL (2.3 times the upper limit of the human therapeutic range) during susceptible periods of embryonic development.
Administration of an oral dose of 200 mg/kg/day or greater (50% of the maximum human daily dose or greater on a mg/m2basis) to pregnant rats during organogenesis produced malformations (skeletal, cardiac, and urogenital) and growth retardation in the offspring. These doses resulted in peak maternal plasma valproate levels of approximately 340 µg/mL or greater (3.4 times the upper limit of the human therapeutic range or greater). Behavioral deficits have been reported in the offspringof rats given a dose of 200 mg/kg/day throughout most of pregnancy. An oral dose of 350 mg/kg/day (approximately 2 timesthe maximum human daily dose on a mg/m2 basis) produced skeletal and visceral malformations in rabbits exposed duringorganogenesis. Skeletal malformations, growth retardation, and death were observed in rhesus monkeys following administra-tion of an oral dose of 200 mg/kg/day (equal to the maximum human daily dose on a mg/m2 basis) during organogenesis. Thisdose resulted in peak maternal plasma valproate levels of approximately 280 µg/mL (2.8 times the upper limit of the humantherapeutic range).
The prescribing physician will wish to weigh the benefits of therapy against the risks in treating or counseling women of childbearing potential. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, thepatient should be apprised of the potential hazard to the fetus.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In indi-vidual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose aserious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannotbe said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
Tests to detect neural tube and other defects using current accepted procedures should be considered a part of routine pre- natal care in childbearing women receiving valproate.
PRECAUTIONS
Hepatic Dysfunction
See BOXED WARNING, CONTRAINDICATIONS and WARNINGS.
General
Because of reports of thrombocytopenia (see WARNINGS), inhibition of the secondary phase of platelet aggregation, and
abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiat-
ing therapy and at periodic intervals. It is recommended that patients receiving DEPAKOTE be monitored for platelet count
and coagulation parameters prior to planned surgery. In a clinical trial of DEPAKOTE as monotherapy in patients with
epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets
≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In theremaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopeniaappeared to increase significantly at total valproate concentrations of ≥ 110 µg/mL (females) or ≥ 135 µg/mL (males). Evi-dence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or with-drawal of therapy.
Hyperammonemia with or without lethargy or coma has been reported and may be present in the absence of abnormal liver function tests. Asymptomatic elevations of ammonia are more common and when present require more frequent monitoring.
If clinically significant symptoms occur, DEPAKOTE therapy should be modified or discontinued.
Since DEPAKOTE may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy.
(See PRECAUTIONS-Drug Interactions.)
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is Suicidal ideation may be a manifestation of certain psychiatric disorders, and may persist until significant remission of symptoms occurs. Close supervision of high risk patients should accompany initial drug therapy.
Information for Patients
Since DEPAKOTE products may produce CNS depression, especially when combined with another CNS depressant (eg, alco-
hol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous
machinery, until it is known that they do not become drowsy from the drug.
Migraine Patients: Since DEPAKOTE has been associated with certain types of birth defects, female patients of child-bear-
ing age considering the use of DEPAKOTE for the prevention of migraine should be advised to read the Patient Information
Leaflet, which appears as the last section of the labeling.
Drug Interactions
Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may
increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clear-ance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiv-ing polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary meta-bolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously beingreported.
Drugs for which a potentially important interaction has been observed:Aspirin - A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatricpatients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction wasincreased 4-fold in the presence of aspirin compared to valproate alone. The ß-oxidation pathway consisting of 2-E-valproicacid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate aloneto 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered.
Felbamate - A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 µg/mL) compared to valproatealone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 µg/mL (another16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin - A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dos- ing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may benecessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed:Antacids - A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Triso-gel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
Chlorpromazine - A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.
Haloperidol - A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiv- ing valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine - Cimetidine and ranitidine do not affect the clearance of valproate.
Effects of Valproate on Other DrugsValproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co-administration on the pharma- cokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interac-tions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed:Carbamazepine/carbamazepine-10,11-Epoxide - Serum levels of carbamazepine (CBZ) decreased 17% while that of carba-mazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam - The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history Diazepam - Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-adminis- tration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6).
Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presenceof valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide - Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-lifeof ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate andethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of bothdrugs. Lamotrigine - In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-admin-istered with valproate.
Phenobarbital - Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excretedunchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum con- centrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity.
Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.
Phenytoin - Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoinincreased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin werereduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide - From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.
Warfarin - In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic rele- vance of this is unknown; however, coagulation tests should be monitored if DEPAKOTE therapy is instituted in patients tak-ing anticoagulants.
Zidovudine - In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed:Acetaminophen - Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concur-rently administered to three epileptic patients.
Amitriptyline/Nortriptyline - Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptylineresulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely beenassociated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantlywith amitriptyline.
Clozapine - In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium - Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam - Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
Oral Contraceptive Steroids - Administration of a single-dose of ethinyloestradiol (50 µg)/levonorgestrel (250 µg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Valproic acid was administered orally to Sprague Dawley rats and ICR (HA/ICR) mice at doses of 80 and 170 mg/kg/day
(approximately 10 to 50% of the maximum human daily dose on a mg/m2 basis) for two years. A variety of neoplasms were
observed in both species. The chief findings were a statistically significant increase in the incidence of subcutaneous fibrosar-
comas in high dose male rats receiving valproic acid and a statistically significant dose-related trend for benign pulmonary ade-
nomas in male mice receiving valproic acid. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and
did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chro-
matid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not
observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with
epilepsy. The biological significance of increase in SCE frequency is not known.
Fertility
Chronic toxicity studies in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at
oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum human daily dose on
a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the maximum human daily dose or greater on
a mg/m2 basis). Segment I fertility studies in rats have shown doses up to 350 mg/kg/day (approximately equal to the maxi-
mum human daily dose on a mg/m2 basis) for 60 days to have no effect on fertility. THE EFFECT OF VALPROATE ON TES-
TICULAR DEVELOPMENT AND ON SPERM PRODUCTION AND FERTILITY IN HUMANS IS UNKNOWN.
Pregnancy
Pregnancy Category D: See WARNINGS.
Nursing Mothers
Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1-10% of serum concentrations. It
is not known what effect this would have on a nursing infant. Consideration should be given to discontinuing nursing when
divalproex sodium is administered to a nursing woman.
Pediatric
Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing
fatal hepatotoxicity, especially those with the aforementioned conditions (see BOXED WARNING). When DEPAKOTE is
used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be
weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepato-
toxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain tar- geted total and unbound valproic acid concentrations.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Inter- pretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism andprotein binding.
The safety and effectiveness of DEPAKOTE for the treatment of acute mania has not been studied in individuals below the The safety and effectiveness of DEPAKOTE for the prophylaxis of migraines has not been studied in individuals below the The basic toxicology and pathologic manifestations of valproate sodium in neonatal (4-day old) and juvenile (14-day old) rats are similar to those seen in young adult rats. However, additional findings, including renal alterations in juvenile rats andrenal alterations and retinal dysplasia in neonatal rats, have been reported. These findings occurred at 240 mg/kg/day, a dosageapproximately equivalent to the human maximum recommended daily dose on a mg/m2 basis. They were not seen at 90 mg/kg, or 40% of the maximum human daily dose on a mg/m2 basis.
Geriatric
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipo-
lar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of
patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate
was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether
they result from preexisting medical illness and concomitant medication use among these patients.
In a double-blind, multicenter trial of valproate, in elderly patients with dementia, doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. Patients experienced a significant increase in somnolence and discontinuations for somnolence
compared to placebo. In some patients these events were also associated with reduced nutritional intake and weight loss. There
was a trend for the patients who experienced these events to have lower albumin concentrations, valproate clearance, and to be
older than patients who better tolerated a given dose. In elderly patients, dosage should be increased more slowly and with
monitoring for possible adverse events. (See DOSAGE AND ADMINISTRATION).
There is insufficient information available to discern the safety and effectiveness of DEPAKOTE for the prophylaxis of ADVERSE REACTIONS
Mania
The incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clini-
cal trials of DEPAKOTE in the treatment of manic episodes associated with bipolar disorder. The adverse events were usually
mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of prema-
ture termination due to intolerance were not statistically different between placebo, DEPAKOTE, and lithium carbonate. A total
of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, DEPAKOTE, and lithium carbonate
groups, respectively.
Table 1 summarizes those adverse events reported for patients in these trials where the incidence rate in the DEPAKOTE- treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the DEPAKOTE-treatedgroup was statistically significantly greater than the placebo group. Vomiting was the only event that was reported by signifi-cantly (p ≤ 0.05) more patients receiving DEPAKOTE compared to placebo. Adverse Events Reported by > 5% of DEPAKOTE-Treated
Patients During Placebo-Controlled Trials of Acute Mania1
DEPAKOTE
Adverse Event
The following adverse events occurred at an equal or greater incidence for placebo than for DEPAKOTE: back pain,headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse events were reported by greater than 1% but not more than 5% of the 89 divalproex sodium-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.
Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation.
Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess.
Hemic and Lymphatic System: Ecchymosis.
Metabolic and Nutritional Disorders: Edema, peripheral edema.
Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching.
Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinkingabnormalities, vertigo.
Respiratory System: Dyspnea, rhinitis.
Skin and Appendages: Alopecia, discoid lupus erythematosis, dry skin, furunculosis, maculopapular rash, seborrhea.
Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.
Urogenital System: Dysmenorrhea, dysuria, urinary incontinence.
Migraine
Based on two placebo-controlled clinical trials and their long term extension, DEPAKOTE was generally well tolerated with
most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to DEPAKOTE in the placebo-controlled
trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term
extension study, the adverse events reported as the primary reason for discontinuation by ≥1% of 248 DEPAKOTE-treated
patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT
and/or SGPT (1%), and depression (1%).
Table 2 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in the DEPAKOTE-treated group was greater than 5% and was greater than that for placebo patients.
Adverse Events Reported by >5% of DEPAKOTE-Treated Patients
During Migraine Placebo-Controlled Trials with a Greater
Incidence Than Patients Taking Placebo1
Body System
Depakote
Gastrointestinal System
Nervous System
1 The following adverse events occurred in at least 5% of DEPAKOTE-treated patients and at an equal or greater incidence for placebo than for DEPAKOTE: flu syndrome and pharyngitis.
The following additional adverse events were reported by greater than 1% but not more than 5% of the 202 divalproex sodium-treatedpatients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise.
Cardiovascular System: Vasodilatation.
Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis.
Hemic and Lymphatic System: Ecchymosis.
Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase.
Musculoskeletal System: Leg cramps and myalgia.
Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthe- sia, speech disorder, thinking abnormalities, and vertigo.
Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis.
Skin and Appendages: Pruritus and rash.
Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, DEPAKOTE was generally
well tolerated with most adverse events rated as mild to moderate in severity. Intolerance was the primary reason for discon-
tinuation in the DEPAKOTE-treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse events which were reported by ≥ 5% of DEPAKOTE-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of com-plex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to deter-mine whether the following adverse events can be ascribed to DEPAKOTE alone, or the combination of DEPAKOTE and otherantiepilepsy drugs.
Adverse Events Reported by ≥ 5% of Patients Treated
with DEPAKOTE During Placebo-Controlled Trial of
Adjunctive Therapy for Complex Partial Seizures
Depakote (%)
Placebo (%)
Body System/Event
Body as a Whole
Gastrointestinal System
Nervous System
Respiratory System
Table 4 lists treatment-emergent adverse events which were reported by ≥ 5% of patients in the high dose DEPAKOTE group,and for which the incidence was greater than in the low dose group, in a controlled trial of DEPAKOTE monotherapy treat-ment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of thetrial, it is not possible, in many cases, to determine whether the following adverse events can be ascribed to DEPAKOTE alone,or the combination of DEPAKOTE and other antiepilepsy drugs. Adverse Events Reported by ≥ 5% of Patients in the High Dose
Group in the Controlled Trial of DEPAKOTE Monotherapy for
Complex Partial Seizures1
High Dose (%)
Low Dose (%)
Body System/Event
Body as a Whole
Digestive System
Hemic/Lymphatic System
Metabolic/Nutritional
Nervous System
Respiratory System
Skin and Appendages
Special Senses
Headache was the only adverse event that occurred in ≥ 5% of patients in the high dose group and at an equal or greaterincidence in the low dose group.
The following additional adverse events were reported by greater than 1% but less than 5% of the 358 patients treated withDEPAKOTE in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personal- Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.
Other Patient Populations
Adverse events that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other
sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion.
These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipationhave been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. Theadministration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related),hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, “spots before eyes”, dysarthria, dizziness, confusion, hypes-thesia, vertigo, incoordination, and parkinsonism. Rare cases of coma have occurred in patients receiving valproate alone or inconjunction with phenobarbital. In rare instances encephalopathy with fever has developed shortly after the introduction of val-proate monotherapy without evidence of hepatic dysfunction or inappropriate plasma levels; all patients recovered after thedrug was withdrawn.
Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-John- son syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant tak-ing valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death wasreported in a 35 year old patient with AIDS taking several concomitant medications and had with a history of multiple cuta-neous drug reactions.
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage (see PRECAUTIONS - General
and Drug Interactions). Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia includ-
ing macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, and acute inter-
mittent porphyria.
Hepatic: Minor elevations of transaminases (eg, SGOT and SGPT) and LDH are frequent and appear to be dose-related.
Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests.
These results may reflect potentially serious hepatotoxicity (see WARNINGS).
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnor- mal thyroid function tests (see PRECAUTIONS).
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been estab- Pancreatic: Acute pancreatitis including fatalities.
Metabolic: Hyperammonemia (see PRECAUTIONS), hyponatremia, and inappropriate ADH secretion.
There have been rare reports of Fanconi’s syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyper-
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported.
Other: Anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, and fever.
OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; howeverpatients have recovered from valproate levels as high as 2120 µg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time sinceingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary out-put.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theo- retically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.
DOSAGE AND ADMINISTRATION
Mania
DEPAKOTE tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should
be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the
desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical
response with a trough plasma concentration between 50 and 125 µg/mL. Maximum concentrations were generally achieved
within 14 days. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during DEPAKOTE treatment of an acute manic episode. While it is generally agreed that pharmacologicaltreatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention ofnew manic episodes, there are no systematically obtained data to support the benefits of DEPAKOTE in such longer-term treat-ment. Although there are no efficacy data that specifically address longer-term antimanic treatment with DEPAKOTE, thesafety of DEPAKOTE in long-term use is supported by data from record reviews involving approximately 360 patients treated with DEPAKOTE for greater than 3 months. Epilepsy
DEPAKOTE tablets are administered orally. DEPAKOTE has been studied as monotherapy and adjunctive therapy in complex
partial seizures, and in simple and complex absence seizures in adults and adolescents. As the DEPAKOTE dosage is titrated
upward, concentrations of phenobarbital, carbamazepine, and/or phenytoin may be affected (see PRECAUTIONS - Drug
Interactions).
Complex Partial Seizures: For adults and children 10 years of age or older.
Monotherapy (Initial Therapy): DEPAKOTE has not been systematically studied as initial therapy. Patients should initiate
therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.
Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range
(50 to 100 µg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 µg/mL in females and 135 µg/mL in males. The benefit of improved seizure control with higher doses should be weighedagainst the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy: Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whetheror not they are in the usually accepted therapeutic range (50 - 100 µg/mL). No recommendation regarding the safety of val-proate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily bereduced by approximately 25% every 2 weeks. This reduction may be started at initiation of DEPAKOTE therapy, or delayedby 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawalof the concomitant AED can be highly variable, and patients should be monitored closely during this period for increasedseizure frequency.
Adjunctive Therapy: DEPAKOTE may be added to the patient’s regimen at a dosage of 10 to 15 mg/kg/day. The dosage maybe increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved atdaily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured todetermine whether or not they are in the usually accepted therapeutic range (50 to 100 µg/mL). No recommendation regardingthe safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should begiven in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to DEPAKOTE, no adjustment of carbamazepine or phenytoin dosage was needed (see CLINICAL
STUDIES). However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs
(see Drug Interactions), periodic plasma concentration determinations of concomitant AEDs are recommended during the
early course of therapy (see PRECAUTIONS - Drug Interactions).
Simple and Complex Absence Seizures: The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by
5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage
is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from
50 to 100 µg/mL. Some patients may be controlled with lower or higher serum concentrations (see CLINICAL PHARMA-
COLOGY).
As the DEPAKOTE dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected (see PRECAUTIONS).
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving DEPAKENE (valproic acid) therapy, DEPAKOTE tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on DEPAKOTE tablets, a dosing schedule of two or threetimes a day may be elected in selected patients.
Migraine
DEPAKOTE tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may bene-
fit from doses up to 1000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy.
General Dosing Advice
Dosing in Elderly Patients - Due to a decrease in unbound clearance of valproate, the starting dose should be reduced; the ulti-
mate therapeutic dose should be achieved on the basis of clinical response.
Dose-Related Adverse Events - The frequency of adverse effects (particularly elevated liver enzymes and thrombocytope- nia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentra-
tions of ≥ 110 µg/mL (females) or ≥ 135 µg/mL (males) (see PRECAUTIONS). The benefit of improved therapeutic effect
with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation - Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
HOW SUPPLIED
DEPAKOTE tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets:
Bottles of 100 .(NDC 0074-6212-13)
Abbo-Pac® unit dose packages of
100 .(NDC 0074-6212-11).
250 mg peach-colored tablets:
Bottles of 100 .(NDC 0074-6214-13)
Bottles of 500 .(NDC 0074-6214-53)
Abbo-Pac® unit dose packages of
100 .(NDC 0074-6214-11).
500 mg lavender-colored tablets:
Bottles of 100 .(NDC 0074-6215-13)
Bottles of 500 .(NDC 0074-6215-53)
Abbo-Pac® unit dose packages of
100 .(NDC 0074-6215-11).
Recommended storage: Store tablets below 86˚F (30˚C).
Patient Information Leaflet
Important Information for Women Who Could Become Pregnant
About the Use of Depakote® (divalproex sodium) Tablets for Migraine
Please read this leaflet carefully before you take Depakote® (divalproex sodium) tablets. This leaflet provides a summary ofimportant information about taking Depakote for migraine to women who could become pregnant. Depakote is also prescribedfor uses other than those discussed in this leaflet. If you have any questions or concerns, or want more information aboutDepakote, contact your doctor or pharmacist.
Information For Women Who Could Become Pregnant
Depakote is used to prevent or reduce the number of migraines you experience. Depakote can be obtained only by prescrip-
tion from your doctor. The decision to use Depakote for the prevention of migraine is one that you and your doctor should
make together, taking into account your individual needs and medical condition.
Before using Depakote, women who can become pregnant should consider the fact that Depakote has been associated with
birth defects, in particular, with spina bifida and other defects related to failure of the spinal canal to close normally.
Although the incidence is unknown in migraine patients treated with Depakote, approximately 1 to 2% of children born
to women with epilepsy taking Depakote in the first 12 weeks of pregnancy had these defects (based on data from the
Centers for Disease Control, a U.S. agency based in Atlanta). The incidence in the general population is 0.1 to 0.2%.
Information For Women Who Are Planning to Get Pregnant• Women taking Depakote for the prevention of migraine who are planning to get pregnant should discuss with their doctor temporarily stopping Depakote, before and during their pregnancy.
Information For Women Who Become Pregnant While Taking Depakote• If you become pregnant while taking Depakote for the prevention of migraine, you should contact your doctor immediately.
Other Important Information About Depakote Tablets• Depakote tablets should be taken exactly as it is prescribed by your doctor to get the most benefits from Depakote and • If you have taken more than the prescribed dose of Depakote, contact your hospital emergency room or local poison center • This medication was prescribed for your particular condition. Do not use it for another condition or give the drug to others.
Facts About Birth DefectsIt is important to know that birth defects may occur even in children of individuals not taking any medications or without anyadditional risk factors. Facts About MigraineAbout 23 million Americans suffer from migraine headaches. About 75% of migraine sufferers are women. A migraine isdescribed as a throbbing headache that gets worse with activity. Migraine may also include nausea and/or vomiting as well assensitivity to light and sound. Migraine usually happens about once a month, but some people may have them as often as onceor twice a week. Often, the symptoms from a migraine can cause people to miss work or school. If you have frequentmigraines, or if acute treatment is not working for you, your doctor may prescribe a preventative therapy. Preventative (pro-phylactic) treatment is used to prevent attacks and reduce the frequency and severity of headache events.
This summary provides important information about the use of Depakote for migraine to women who could become pregnant.
If you would like more information about the other potential risks and benefits of Depakote, ask your doctor or pharmacist tolet you read the professional labeling and then discuss it with them. If you have any questions or concerns about takingDepakote, you should discuss them with your doctor.
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Source: http://www.migraines.ws/treatment/pdfs/depakote.pdf